Pharmaceutical formulations in hydroxypropylmethylcellulose capsules

ABSTRACT

An oral pharmaceutical formulation, which comprises, in a hydroxypropylmethylcellulose capsule, a camptothecin analogue dispersed or solubilized in a semi-solid matrix of a polyethyleneglycol with a molecular weight ranging from 400 to 20000.

This application is a 371 of PCT/EP00/06590, filed Jul. 11, 2000.

FIELD OF THE INVENTION

The present invention relates to oral dosage forms for camptothecin(CPT) analogues, such as, for example,(S)-[1,4′-Bipiperidine]-1′-carboxylic acid,4,11-Diethyl-3,4,12,14-tetradydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-ylester, monohydrochloride, trihydrate also known as irinotecanhydrochloride trihydrate or CPT-11, in hydroxypropylmethylcellulosecapsules.

BACKGROUND OF THE INVENTION

CPT-11 is a water-soluble pro-drug of SN-38 (7-ethyl-10-hydroxy-CPT), abiologically potent derivative of the anticancer agent CPT, atopoisomerase I inhibitor. CPT-11 was proven efficacious in a variety ofmalignancies. Its clinical efficacy has been highlighted by the factthat CPT-11 is the first new active drug to obtain marketing approval inforty years for colorectal cancer.

The intravenous drug form of CPT-11 is currently used for the treatmentof colorectal cancer.

It is well known that parenteral administration of antitumor drugs isassociated with some intrinsic disadvantages and drawbacks, e.g.,patient discomfort or the requirement for the patient to travel to thephysician's office for drug administration, with obvious results inpatient inconvenience. Thus the need has arisen to find oralformulations of antitumoral drugs that would allow longer dosingregimens, as with continuous infusion, but without the inconvenience orthe discomfort of the patient.

Classic oral formulations are, for example, solid oral dosage forms,that are medication delivery systems presented as solid dose unitsreadily administered by mouth. The group includes tablets, capsules,cachets and pills, as well as bulk or unit-dose powders and granules.The group constitutes the most popular form of presentation, and tabletsand capsules account for the greatest number of preparations in thiscategory.

It has long been known in the pharmaceutical industries that capsulesare a convenient form for the oral administration of a variety of activeagents because of their relative ease of manufacture (compared withother dosage forms such as tablets), flexibility of size and dose.Capsules have traditionally been used for powder or granuleformulations, but, in recent years, capsules have been adapted tocontain the active ingredient in the form of paste, semi-solid or liquidformulation.

Since, for example, CPT-11 is classified as a class I cytotoxic agent,any form of leakage from the dosage form would present a safety concern.

Therefore, formulations as tablets or powder-filled capsules are not assafe and user-friendly as semi-solid filled capsules, since the risks ofleakage of the active ingredient from the unit dosage form, both duringmanufacturing and distribution, is extremely high.

Thus, in light of the above-mentioned problem about the safe handling ofCPT-11, it is desirable to formulate CPT-11 as a semi-solid dispersionor solution to be filled into capsules. In particular, a thermoplastichot-melt type capsule formulation would result in enhanced stability andminimization of leakage concerns.

Furthermore, it is known that the presence of certain active principlesand/or of certain ingredients in the filling medium can promotecross-linking in the capsule gelatin shell with the passage of timeand/or under stressed conditions. When cross-linking occurs, the gelatinshell becomes less soluble in aqueous media. Cross-linking causesretardation of the disintegration of the capsule shell, and thusretardation of the dissolution of the capsule contents, relative toidentical capsules, which have not been subjected to aging or storing atstressed conditions (i.e. temperature and humidity).

Thus, when a filled gelatin capsule contains an ingredient, whichpromotes cross-linking in the gelatin shell, such as, e.g. apolyethylenglycol (PEG), it is challenging to prepare a formulation,which does not show retarded disintegration and/or dissolution when theformulation grows old.

There is therefore a need to prepare a safe and stable oral encapsulatedformulation containing a CPT analogue which does not present neitherleakage nor stability problems.

The present invention fulfills such a need by providing stable oralpharmaceutical formulations of CPT analogues which avoid chemicalinteraction between the active Ingredient and/or the excipients withcapsule shells and maintain the dissolution performances of theformulations with aging.

DESCRIPTION OF THE INVENTION

In one aspect of this invention there is provided an oral pharmaceuticalformulation, which comprises a camptothecin analogue dispersed orsolubilised in a semi-solid matrix, filled into ahydroxypropyl-methylcellulose (HPMC) capsule.

The camptothecin analogue of the present invention is selected from thegroup comprising: CPT-11, topoteca-n, SN-38, SN-22, 9-amino-20(S)-CPTand 9-nitro-20(S)-CPT.

In particular, the present invention provides an oral pharmaceuticalformulation, which comprises CPT-11, dispersed or solubilized into asemi-solid matrix, filled into a hydroxypropylmethylcellulose capsule.

A suitable semi-solid matrix for the formulation according to thisinvention can be, e.g., a polyethylenglycol (PEG) In the molecularweight range between 400 and 20000, preferably between 1000 and 4000 andspecifically 3000, optionally in combination with suitable excipientsfor semi-solid matrix compositions. Suitable excipients can be, forexample, pharmaceutical or food-grade oils, e.g. soya or fractionatedcoconuts oils; surfactants, e.g. polysorbates; poloxamers, i.e.polyoxyethylene-polyoxypropylene copolymers; solubilising agent, e.g.ethanol and triacetin; natural or synthetic glycerides, e.g.fractionated medium chain glycerides or saturated polyglycol glycerides;or phospholipids.

The formulations according to the invention may be prepared by means ofconventional techniques well known to one of ordinary skill in the art.

Typically, the semi-solid matrix to be filled into capsules may beprepared by adding the camptothecin analogue to a molten homogeneousmixture of the excipients. This is then followed by through mixing ofthe molten mass and capsule filling using standard techniques.Hydroxypropylmethylcellulose capsules are chosen as primary packagingfor such a formulation.

For example, the amount of CPT-11 may be in the range of from about 0.2to about 200 mg, preferably from about 20 to about 100 mg per unit dose.

Generally, a semi-solid matrix formulation is a dispersion or a solutionof the active ingredient in thermosoftening hot melt inert carrierprepared by mixing or homogenization.

The obtained semi-solid matrix is therefore filled Into caosuies asliquid using fluid-filling pumps and allowed to solidify at ambienttemperature. The major advantage of semi-solid formulations is thesafety during manufacturing, being the drug dispersed or dissolved in aliquid mass. At ambient condition such a formulation is solid, providingbetter chemical stabilitze and minimizing leakage problems.

Selection of suitable excipients for semi-solid matrix formulations iscommonly based on physico-chemical, rheological and thermal properties,compatibility with drug and capsule shell as well as on the requireddrug release profile and bioavailability characteristics of the finaldosage form.

In general, thermosoftening materials should have a mewling temperaturein the range of about 30° C. to 70° C. and a quite rapid solidificationtime at ambient condition to avoid any leakage phenomena from capsuleafter filling and/or during the sealing operation.

Drugs or excipients containing aldehyde groups, or producing aldehyde indecomposition, promote cross-linking in conventional capsules shellsmade from gelatin, forming a thin insoluble membrane that may delaydissolution.

Moreover, in semi-solid matrix formulations any interaction between thecomponents and the capsule shell is magnified in comparison to powderfilled capsules, being the surface contact area between the activeingredients/excipients and the gelatin shell higher.

It can be considered as an unexpected result the fact that theformulations of the present invention are able to guarantee themaintenance of the physico-chemical characteristics of the formulationsduring manufacturing and storage and to overcome the undesiredcross-linking effect, that is practically highlighted by a reduced drugrelease profile from the dosage forms, especially with aging.

Dissolution rate test results, recovered during accelerated stabilitystudies, as reported in the Examples 1 to 5, clearly demonstrate theincreased stability shown by CPT-11 formulations placed intohydroxypropylmethylcellulose capsules according to the invention, whencompared with the same CPT-11 formulations placed into conventional hardgelatin capsules.

The following examples are given with the purpose to better illustratethe invention but in no way they must be considered as a limitation ofthe scope of the invention itself.

It is to be understood that, although the examples reported in thedescription consider the use of CPT-11 as a representative compound ofthe camptothecin analogue compounds, the formulation approach accordingto the invention may be analogously applicable to other camptotheclnanalogues.

EXAMPLE 1

In the following table 1, the dissolution rate test results, recoveredduring an accelerated stability study, on Batch ND1216 (CPT-11semi-solid matrix formulation in PEG100—100 mg CPT-11/capsule—HardGelatin Capsule as primary packaging) are shown.

The results are expressed as percent labeled amount (Release %) and itsrelative standard deviation percent (r.s.d. %) of the active dissolvedafter 60 minutes in simulated gastric fluid (SGF) without pepsin.

TABLE 1 Storage Dissolution (Time/conditions) Release (%) r.s.d. (%)medium Initial 100.2 0.3 SGF without pepsin 1 month/55° C. 57.0 64.0 SGFwithout pepsin 1 month/ 74.6 20.3 SGF without 40° C. + 75% R.H. pepsinR.H. = Relative Humidity

As evident from the above-tabulated data, the release performances ofthe active from hard gelatin capsules decrease with aging. No chemicaldegradation of the active, that could justify such a reduction in thedissolution release performances, was observed.

EXAMPLE 2

In the following table 2, the dissolution rate test results, recoveredduring an accelerated stability study, on Batch D54G01 (CPT-11semi-solid matrix formulation in PEG100—50 mg CPT-11/capsule—HardGelatin Capsule as primary packaging) are shown.

The results are expressed as percent labeled amount (Release %) and itsrelative standard deviation percent (r.s.d. %) of the active dissolvedafter 60 minutes in simulated gastric fluid (SGF) without pepsin.

TABLE 2 Storage Dissolution (Time/conditions) Release (%) r.s.d. (%)medium Initial 100.1 0.4 SGF without pepsin 1 month/  56.0 67.4 SGFwithout 40° C. + 75% R.H. pepsin 1 month/  97.5 (1) 2.2 SGF without 40°C. + 75% R.H. pepsin R.H. = Relative Humidity (1) Dissolution performedon ‘capsule content’

As evident from the above-tabulated data, the release performances ofthe active from hard gelatin capsules decrease with aging. No chemicaldegradation of the active, that could justify such reduction in thedissolution release performances, was observed.

The good dissolution performance of the formulation stored for 1 monthat 40° C. 75% R.H., by removing the content from the gelatin shellbefore the dissolution testing, is the clear demonstration that thereduction in the release profile is exclusively due to the partialinsolubilization of the capsule shell induced by the cross-linkingprocess.

EXAMPLE 3

In the following table 3, the dissolution rate test results, recoveredduring an accelerated stability study on Batch ND1283 (CPT-11 semi-solidmatrix formulation in PEG3000—100 mg CPT-11/capsule—Hard Gelatin Capsuleas primary packaging) are shown.

The results are expressed as percent labeled amount (Release %) and asminimum and maximum release percent value of the active dissolved after60 minutes in simulated gastric fluid (SGF) with and without pepsin.

The use of pepsin is allowed by regulatory authorities in order toovercome the cross-linking issue of hard gelatin capsules. In fact, ifthe cross-linked gelatin is disrupted by the mechanical forces ofgastric emptying or is broken down by digestive enzymes, its formationwould not affect absorption and bioavailability of the active. TheUnited States rood and Drug Administration (FDA)/Industry GelatinCapsule Working Group concluded that formation of an insoluble membranecould be considered to have a negligible impact on drug bioavailabilityif the capsules dissolved during the ‘two-tiered dissolution test’ whichemploys a methods containing digestive enzymes.

TABLE 3 Minimum and Storage maximum release Dissolution(Time/conditions) Release (%) (%) value medium Initial 92.1 87.9-97.4SGF without pepsin 1 month/55° C. 9.8  5.2-16.8 SGF without pepsin 1month/ 6.3  3.7-11.5 SGF without 40° C. + 75% R.H. pepsin 1 month/55° C.89.6 91.2-97.4 SGF with pepsin 1 month/ 91.9 89.2-96.1 SGF with 40° C. +75% R.H. pepsin 3 month/ 69.6 37.6-89.9 SGF with 40° C. + 75% R.H.pepsin R.H. = Relative Humidity

It is clearly evident from the above-tabulated data that the addition ofpepsin to the dissolution medium is no sufficient to overcome theproblem. After 3 month storage at 40° C. and 75%R.H., not even theaddition of pepsin to the dissolution medium has allowed obtaining acomplete release of the active from the formulation. No chemicaldegradation of the active, that could justify such reduction in thedissolution release performances, was observed.

EXAMPLE 4

In the following table 4, the dissolution rate test results, recoveredduring an accelerated stability study, on Batch ND1651 (CPT-11semi-solid matrix formulation in PEG3000—50 mgCPT-11/capsule—Hydroxypropylmethylcellulose Capsule as primarypackaging) are shown.

The results are expressed as percent labeled amount (Release %) and itsrelative standard deviation percent (r.s.d. %) of the active dissolvedafter 60 minutes in simulated gastric fluid (SGF) without pepsin.

TABLE 4 Storage Dissolution (Time/conditions) Release (%) r.s.d. (%)medium Initial 101.5 2.5 SGF without pepsin 1 month/55° C. 100.2 10.5SGF without pepsin 3 month/ 106.5 1.9 SGF without 40° + 75% R.H. pepsin

It is clearly evident from the above-tabulated data that there is notany influence of aging on the release performances of the active fromthe HPMC formulation. The same unit dosage strength (i.e. 50 mgCPT-11/capsule), packed into hard gelatin capsule, showed reduceddissolution behavior already after 1 month storage at 40° C.+75% R.H.(as above shown in Example 2), while a 3 month storage at the samecondition has no effect at all on the dissolution performance of theformulation manufactured into hydroxypropylmethylcellulose capsule. Nochemical degradation of the active was observed.

EXAMPLE 5

In the following table 5, the dissolution rate test results, recoveredduring an accelerated stability study, on Batch ND1655 (CPT-11semi-solid matrix formulation in PEG3000—100 mgCPT-11/capsule—Hydroxypropylmethylcellulose Capsule as primarypackaging) are shown.

The results are expressed as percent labeled amount (Release %) and itsrelative standard deviation percent (r.s.d. %) of the active dissolvedafter 60 minutes in simulated gastric fluid (SGF) without pepsin.

TABLE 5 Storage Dissolution (Time/conditions) Release (%) r.s.d. (%)medium Initial 90.3 4.1 SGF without pepsin 1 month/55° C. 90.2 1.6 SGFwithout pepsin 1 month/ 94.6 2.0 SGF without 40° C. + 75% R.H. pepsin 3month/ 92.3 2.0 SGF without 40° + 75% R.H. pepsin

It is clearly evident from the above-tabulated data that there is notany influence of aging on the release performances of the active fromthe HPMC encapsulated formulation. The same unit dosage strength (i.e.100 mg CPT-11/capsule), packed into hard gelatin capsule, showed reduceddissolution behavior already after 1 month storage at 40° C.+75% R.H.(as above shown in Example 3), while a 3 month storage at the samecondition has no effect at all on the dissolution performance of theformulation manufactured into hydroxypropylmethylcellulose capsule. Nochemical degradation of the active was observed.

EXAMPLE 6

In this example, typical semi-solid filling matrices, suitable forhydroxypropylmethylcellulose capsules, are shown. The below mentionedformulae are not intended to be exhaustive or to limit anyway the scopeof the invention itself.

mg per capsule mg per capsule FORMULA A CPT-11  50 mg 100 mgPolyethylenglycol3000 575 mg 525 mg Fill weight per capsule 625 mg 625mg FORMULA B CPT-11 50 mg 100 mg Polyethylenglycol1000 575 mg 525 mgFill weight per capsule 625 mg 625 mg FORMULA C CPT-11  50 mg 100 mgPolyethylenglycol3000 520 mg 470 mg Triacetin  50 mg  50 mgPolysorbate80  5 mg  5 mg Fill weight per capsule 625 mg 625 mg FORMULAD CPT-11  50 mg 100 mg Polyethylenglycol3000 520 mg 470 mgPolyethylenglycol400  50 mg  50 mg Polysorbate80  5 mg  5 mg Fill weightper capsule 625 mg 625 mg FORMULA E CPT-11  50 mg 100 mgPolyethylenglycol3000 525 mg 475 mg Gelucire44/14  50 mg  50 mg Fillweight per capsule 625 mg 625 mg Hydroxypropylmethylcellulose capsulessize 0

Another aspect of the present invention provides a method for treating atumor in a mammal, including a human, which comprises administering tosaid mammal an oral pharmaceutical formulation of a camptothecinanalogue as described in the present invention.

The formulations according to the invention are useful for treatingneoplastic diseases, reducing tumor burden, preventing or treatingmetastasis of neoplasms and preventing recurrences of tumor/neoplasticgrowths in mammals.

In particular, formulations according to the present invention, whereinthe camptothecin analogue is CPT-11, are suitable for the treatment ofcolorectal cancer.

What is claimed is:
 1. An oral pharmaceutical formulation, whichcomprises: in a hydroxypropylmethylcellulose capsule, a camptothecinanalogue dispersed or solubilized in a semi-solid matrix of apolyethyleneglycol with a molecular weight ranging from 400 to
 20000. 2.A formulation according to claim 1 wherein the camptothecin analogue isCPT-11.
 3. A formulation according to claim 2 which comprises from 0.2to 200 mg per unit dose of CPT-11.
 4. A formulation according to claim 3which comprises from 20 to 100 mg per unit dose of CPT-11.
 5. Aformulation according to claim 1, wherein the polyethyleneglycol has amolecular weight of from 1000 to
 4000. 6. A formulation according toclaim 5 wherein the polyethyleneglycol has a molecular weight of 3000.7. A formulation according to claim 1 which firther comprises anexcipient for the semi-solid matrix.
 8. A formulation according to claim7, wherein the excipient is selected from the group consisting of afood-grade glyceride oil, a surfactant, a solubilizing agent, afractionated medium chain glyceride or a saturated polyglycol glycerideand a phospholipid.
 9. A formulation according to claim 2, wherein theamount of CPT-11 is about 0.2 to about 200 mg per unit dose.
 10. Aformulation according to cliam 9, wherein the amount of CPT-11 is about20 to about 100 mg per unit dose.
 11. A formulation according to claim1, wherein the camptothecin analogue is selected from the groupconsisting of4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-ylester, monohydrochloride, trihydrate (CPT-11);(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4:6,7]indolizino[1,2-b]-quinoline-3,14(4H,12H)-dione(topotecan); 7-ethyl-10-hydroxycamptothecin (SN-38); 9-amino-20(S)-camptothecin and 9-nitro-20(S)-camptothecin.
 12. A method oftreating neoplastic diseases, comprising: administering the oralformulation of claim 1 to a subject suffering from a neoplastic disease.13. A method according to claim 12, wherein the neoplastic disease iscolorectal cancer.
 14. A method of reducing tumors, comprising:administering the oral formulation of claim 1 to a subject having atumor thereby reducing the size of the tumor.
 15. A method of treatingneoplasm metastasis, comprising: administering the oral formulation ofclaim 1 to a subject having suffering from a neoplasm metastasis.
 16. Amethod of preventing recurrences of tumor or neoplastic growths inmammals, comprising: administering the oral formulation of claim 1 to asubject having suffering from a recurrence of a tumor or neoplasmgrowth.